Our group has recently developed an endoscopic polarized spectroscopic scanning (EPSS) instrument. The EPSS instrument gives real time, in vivo, information on the location of high grade dysplasia (HGD), a traditional predictor of adenocarcinoma. This instrument, compatible with existing commercial endoscopes, is based on the technique of light scattering spectroscopy (LSS). LSS successfully demonstrated in a proof-of-principle study the ability to identify pre-cancer in the epithelial tissue of five different organs, including Barrett's esophagus (BE). The EPSS instrument is a significant advance over the single-point instrument in that: (1) it scans the entire esophagus; (2) it integrates the data analysis software with the instrument in order to provide the physician with real time diagnostic information for guiding biopsy; (3) it employs collimated illumination and collection optics, enabling multispectral mapping of epithelial tissue unaffected by peristaltic motion; (4) it incorporates both the polarization technique for removing the unwanted background in the single backscattering LSS signal, and the diffuse reflectance spectroscopy signal, thereby improving the diagnostic assessment capability. In its first test, the new EPSS instrument successfully guided biopsy in the esophagus, detecting and mapping sites of invisible precancerous dysplasia in esophageal epithelium missed by the current standard-of-care. However, in order to establish unbiased characteristics of the new instrument and to provide gastroenterologist with an accurate, motion adjusted real time map of invisible dysplasia in esophageal epithelium, important technological improvements and additional clinical studies are required. For this competitive renewal program we will (1) build an improved portable version of the EPSS instrument, (2) redesign the polarized scanning fiber probe, (3) improve real time histological and diagnostic algorithms and (4) improve real time guidance system. We also will test the ability of the new EPSS instrument to provide the gastroenterologist with an accurate tool to classify patients with BE at risk for future cancer during surveillance endoscopy.